Scientists report today in the journal Genome
Research that they have successfully cloned and characterized a
previously intractable DNA sequence: a 554-kilobase-pair genomic
segment near the centromere of the human Y chromosome. This sequence
contains eight putatively active genes that could be implicated in
sex-associated height differences and gonadal tumor development.

This
pericentromeric gap was one of the few holes remaining in the
"finished" sequence of the human genome reported last October by the
International Human Genome Sequencing Consortium. This "finished"
sequence was the culmination of a 13-year effort to elucidate the order
and orientation of 2.85 billion basepairs that comprise the human
genome. The high-quality sequence spanned more than 99% of the
euchromatic (gene-containing) portion of the genome with an accuracy of
99.999%, but despite this accomplishment, substantial sections of
chromosomal sequences were still missing.
The Y chromosome, a sex chromosome that is specific to the human male,
has posed a particular challenge to researchers attempting to decode
its sequence. It contains an extraordinary abundance of repetitive
elements, including transposons and tandem arrays of satellite
sequences. This highly repetitive, transcriptionally dormant genomic
landscape, termed "heterochromatin," defines approximately two-thirds
of the Y chromosome, including a section spanning the centromere. Such
repetitive sequences, although not recalcitrant to cloning, are
laborious to assemble, requiring meticulous analysis of complex
repeated sequences.
In this case, the challenge was undertaken by a team of scientists led
by Gudrun Rappold, Ph.D., Professor of Human Genetics at the University
of Heidelberg in Germany. Their manuscript describing this work,
published online today and in the February print issue of Genome
Research (www.genome.org), presents the sequencing and analysis of 554
kilobases of previously uncharacterized sequence from the
peri
centromeric region of the Y chromosome. This sequence contains a
450-kilobase "euchromatic island" with eight presumably active genes
flanked by repetitive satellite sequences.
To ensure that this 554-kilobase sequence was in fact missing from the
"finished" human genome sequence and was not a structural polymorphism
present only in a subset of males in the human population, members of
Rappold's laboratory ?including Stefan Kirsch, Ph.D., lead author on
the paper ?tested 100 men of different ethnic origin for the presence
of this 554-kilobase fragment. Indeed, the sequence was present in all
100 individuals tested, but not in any female controls, confirming that
this sequence was a fundamental part of the Y chromosome.
More surprising, however, was Rappold's finding that this "missing"
sequence was not unique to the Y chromosome. Rather, this sequence
exhibited between 95-99% homology to sequences on exactly half (11 of
22) of the other chromosomes in the human genome, including the
pericentromeric regions of autosomes (non-sex chromosomes) 1, 2, 3, 4,
9, 10, 11, 14, 15, 16, and 22. This remarkable similarity can be
attributed to segmental duplications, a phenomenon whereby large
portions of the genome are copied during evolution. Segmental
duplications, which emerged during the past 30 million years of primate
evolution, are significantly enriched in subtelomeric and
pericentromeric sequences, and now comprise approximately 5% of the
human genome, were considered to be one of the biggest obstacles to
finishing the human genome sequence. "The identification of these
segmental duplications suggests an underrepresentation of
pericentromeric regions of the acrocentric chromosomes in the current
human genome sequence," Rappold pointed out.
The current study was designed as part of a long-term effort to
characterize the molecular genetic basis for Y-chromosome-linked
phenotypes. Rappold and colleagues had previously physically mapped the
GCY locus, which is thought to be
the genetic determinant of
sex-related stature differences in humans and is in close proximity to
the Y centromere. In addition, the GBY, or gonadoblastoma locus, which
is responsible for development of tumors associated with the
undifferentiated gonad, has been genetically mapped to the region.
Because the "missing" sequence described in this study contained eight
putatively active genes, further functional testing of these genes may
reveal insights into the genetic basis for stature and gonadoblastoma.
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